Saatja: <
[email protected]>
Saadetud: 09.10.2023 18:41
Adressaat: <
[email protected]>; EDQM SARE-TC <
[email protected]>
Koopia: AMBROSIO Massimo <
[email protected]>; FEHILY Deirdre
<
[email protected]>; VAN DER SPIEGEL Stefaan <Stefaan.VAN-DER-
[email protected]>
Teema: Final report SARE T&C 2022 (data 2021)
Dear competent authorities for tissues and cells,
Please find attached the final report of the SARE exercise on T&C
2022 (data 2021).
As you have thoroughly reviewed the preliminary analysis, you should not
expect mayor changes in this file. We would appreciate if you could take
a final look and provide us your comments (if any) until 23rd October
2023.
Please do not hesitate to contact us or directly EDQM (in copy) for any
question or doubt.
Many thanks and kind regards,
The SoHO team.
European Commission DG SANTE (Health and Food Safety)
Unit D2 Medical Products: quality, safety, innovationOffice address: Rue
Breydel 2, 06/004, B-1049 Brussels/Belgium
EUROPEAN COMMISSION
DIRECTORATE GENERAL FOR HEALTH AND FOOD SAFETY
Directorate B - Health systems, medical products and innovation B4 – Medical
products: quality, safety, innovation
SUMMARY OF THE 2022 ANNUAL REPORTING
OF SERIOUS ADVERSE REACTIONS AND EVENTS
FOR TISSUES AND CELLS
(DATA COLLECTED FROM 01/01/2021 TO 31/12/2021 AND
SUBMITTED TO THE EUROPEAN COMMISSION IN 2022)
1
Table of Contents
1 INTRODUCTION ....................................................................................................................... 5
2 EXECUTIVE SUMMARY ............................................................................................................. 5
3 DATA COLLECTION AND ANALYSIS............................................................................................ 7
4 MAJOR FINDINGS .................................................................................................................... 7
Activity data (denominators) ............................................................................................. 7
4.1.1 Tissues and cells distributed .................................................................................................... 7
4.1.1.1 Replacement tissues and cells........................................................................................... 8
4.1.1.2 Haematopoietic stem cells ................................................................................................ 9
4.1.1.3 Reproductive tissues and cells ........................................................................................ 11
4.1.1.4 Incidence of replacement tissues and cells (per million population) ............................. 13
4.1.2 Number of transplant recipients ............................................................................................ 16
4.1.2.1 Non-reproductive tissues and cells ................................................................................. 16
4.1.1.2 Reproductive tissues and cells ........................................................................................ 16
4.1.3 Trends in the distribution and application of tissues and cells .............................................. 17
4.1.4 Number of tissues and cells processed .................................................................................. 18
Serious adverse reactions in recipients .............................................................................19
4.2.1 General information ............................................................................................................... 20
4.2.2 SAR by category of tissues and cells....................................................................................... 22
4.2.3 SAR by type of reaction .......................................................................................................... 25
4.2.3.1 SAR – replacement tissues and cells ............................................................................... 26
4.2.3.2 SAR – haematopoietic stem cells .................................................................................... 27
4.2.3.3 SAR – reproductive tissues and cells ............................................................................... 28
4.2.3.4 SAR Imputability .............................................................................................................. 30
4.2.4 Deaths of recipients of tissues and cells ................................................................................ 31
4.2.4.1 Deaths following the application of HSC ......................................................................... 31
4.2.4.2 Deaths following the application of reproductive tissues and cells ............................... 31
Serious adverse events .....................................................................................................32
4.3.1 General information ............................................................................................................... 32
4.3.2 SAE by type of event .............................................................................................................. 34
4.3.3 SAE by activity step ................................................................................................................ 36
Serious adverse reactions in donors ..................................................................................39
5 CONCLUSIONS ........................................................................................................................43
2
List of figures
Figure 1. Total number of replacement tissues and cells distributed (units); data 2021 ........................8
Figure 2. Number of skeletal tissues distributed per subcategory (units); data 2021 .............................8
Figure 3. Number of ocular tissues distributed per subcategory (units); data 2021 ...............................9
Figure 4. Number of cardiovascular tissues distributed per subcategory (units); data 2021 ..................9
Figure 5: Other replacement tissues distributed per subcategory (units); data 2021 .............................9
Figure 6. Total number of hematopoietic stem cell units distributed (absolute values and percentage);
data 2021................................................................................................................................................10
Figure 7. Number of peripheral stem cell units distributed by type; data 2021....................................10
Figure 8. Number of bone marrow units distributed by type; data 2021 ..............................................10
Figure 9. Number of cord blood units distributed by type; data 2021 ..................................................11
Figure 10. Number of donor lymphocyte infusion units distributed by type; data 2021 ......................11
Figure 11. Number of other HSC unit distributed by type; data 2021 ...................................................11
Figure 12. Number of sperm units distributed by category (absolute values and percentage); data 2021
................................................................................................................................................................12
Figure 13. Number of embryos distributed by category (absolute values and percentage); data 2021
................................................................................................................................................................12
Figure 14. Total number of reproductive tissues distributed (units); data 2021 ...................................12
Figure 15. Incidence of replacement tissue and cell units (number of units distributed and number of
recipients per million population); data 2021........................................................................................13
Figure 16. Incidence of haematopoietic stem cells (number of units distributed and number of
recipients per million population); data 2021........................................................................................14
Figure 17. Incidence of reproductive cells (number of units distributed and number of recipients per
million population); data 2021 ...............................................................................................................15
Figure 18. Total number of recipients per type of replacement tissue and cells; data 2021 ................16
Figure 19. Total number of recipients per type of hematopoietic stem cells; data 2021......................16
Figure 20. Total number of recipients per type of reproductive tissue and cells; data 2021 ................17
Figure 21. Total number of non-reproductive tissues and cells distributed (units) and number of
recipients of human tissues and cells: 2011-2021 comparative data ....................................................18
Figure 22. Total number of reproductive tissues and cells distributed (units) and number of recipients
of human tissues and cells: 2011-2021 comparative data .....................................................................18
Figure 23. Total number of tissues and cells processed (units): 2011-2021 comparative data ............19
Figure 24. Non-reproductive versus reproductive tissues and cells SAR: 2011-2021 comparative data
................................................................................................................................................................20
Figure 25. Total number of SAR by country in transplant recipients; data 2021 ...................................20
Figure 26. Number of SAR by category of tissue and cells; data 2021...................................................22
Figure 27. Number of SAR per country and category of tissues and cells; data 2021 ...........................22
Figure 28. Number of SAR per subcategory of replacement tissues and cells (absolute values and
percentages of total SAR in recipients); data 2021 ................................................................................23
Figure 29. Number of SAR per subcategory of haematopoietic stem cells (absolute values and
percentage of total SAR in recipients); data 2021 .................................................................................24
Figure 30. Number of SAR per subcategory of reproductive cells (absolute values and percentages of
total SAR in recipients); data 2021 .........................................................................................................25
Figure 31. Distribution of SAR for replacement tissues and cells per type of reaction; data 2021 .......26
Figure 32. Distribution of SAR for haematopoietic stem cells by type of reaction; data 2021 ..............27
Figure 33. Distribution of SAR per type of gametes (partner/non-partner), embryo application; data
2021 ........................................................................................................................................................29
Figure 34. Distribution of SAR per type of gametes (partner/non-partner), sperm application; data 2021
3
................................................................................................................................................................30
Figure 35. Number of tissues processed and number of SAE reported; 2011-2021 comparative data 32
Figure 36. Distribution of SAE by type/specification; 2010-2021 data ..................................................34
Figure 37. SAE types for replacement tissues and cells (absolute values and percentages); data 2021
................................................................................................................................................................34
Figure 38. SAE types for haematopoietic tissues and cells (absolute values and percentage); data 2021
................................................................................................................................................................35
Figure 39. SAE types for reproductive tissues and cells (absolute values and percentage); data 2021 35
Figure 40. Distribution of SAE for replacement tissues and cells by activity step; data 2021 ...............36
Figure 41. Distribution of SAE for haematopoietic stem cells by activity step; data 2021 ....................36
Figure 42. Distribution of SAE for reproductive tissues and cells by activity step; data 2021 ...............37
Figure 43. Distribution of SAE for replacement tissues and cells by activity step and SAE type (absolute
values and percentages); data 2021 ......................................................................................................37
Figure 44. Distribution of SAE for haematopoietic stem cells by activity step and SAE type (absolute
values and percentages); data 2021 ......................................................................................................38
Figure 45. Distribution of for reproductive tissues and cells by activity step and SAE type (absolute
values and percentages); data 2021 ......................................................................................................38
Figure 46. Number of SAR in donors by reporting countries and year; 2011-2021 comparative data .40
Figure 47. SAR in donors per category of donated tissue or cells (units); data 2021 ............................40
Figure 48. Number of SAR per category of tissue and cells and per country; data 2021 ......................40
Figure 49. SAR in donors by type of haematopoietic stem cells and type of reaction; data 2021 ........41
Figure 50. Distribution of SAR in donors by type of reaction in oocytes; data 2021 .............................42
List of tables
Table 1. Number of SAR per 10 000 recipients of replacement tissues and cells; data 2021................21
Table 2. Number of SAR per 10 000 recipients of haematopoietic stem cells; data 2021.....................21
Table 3. Number of SAR per 10 000 recipients of reproductive cells; data 2021 ..................................21
Table 4. Number of SAR by subtype of replacement tissues and cells; data 2021 ................................23
Table 5. Number of SAR by subtype of haematopoietic stem cells; data 2021 .....................................24
Table 6. Number of SAR by subtype of reproductive tissues and cells; data 2021 ................................25
Table 7. Breakdown of SAR in HSC by type and by reaction and HSC subtype; data 2021....................28
Table 8. SAR related to the application of non-partner gametes (absolute values and percentage); data
2021 ........................................................................................................................................................30
Table 9. SAR with imputability level reported per category of tissues and cells; data 2021 .................31
Table 10. Number of SAE per 10 000 replacement tissues and cells processed; data 2021 .................33
Table 11. Number of SAE per 10 000 haematopoietic stem cells processed; data 2021 ......................33
Table 12. Number of SAE per 10 000 reproductive tissues and cells processed; data 2021 .................33
Table 13. SAR in donors of haematopoietic stem cells; data 2021 ........................................................42
Table 14. Type of SAR in donors per subcategory of reproductive tissues and cells; data 2021...........42
List of annexes
Annex 1: Examples of SAE and assigned specification for replacement, HSC and reproductive tissues
and cells………….. ..........................................................................................................................44
4
1 INTRODUCTION
The human application of tissues and cells offers important benefits to the lives of thousands of EU
citizens every year. However, the use of any substance of human origin carries some risk, notably the
potential for transmission of disease from the donor or other potential adverse effects to the recipient.
These risks can be controlled and minimised by the implementation of safety and quality measures, as
laid down in EU legislation. Therefore, vigilance and surveillance systems are critical for ensuring
adequate quality and safety of tissues and cells donated for human application. Such systems should
allow the timely detection of any potential adverse incidents that can pose a risk to the quality and
safety of tissues and cells, as well as the investigation of root cause(s) and implementation of effective
corrective and preventive measures, making them an indispensable element of any quality system.
In line with the obligations defined in the legislation, 1 EU member states (MS) submit an annual report
to the European Commission (hereinafter referred to as “the Commission”) on Serious Adverse
Reactions (SAR) and Serious Adverse Events (SAE) – collectively referred to as SARE – from the previous
year, compiled at national level by each National Competent Authority (NCA).
The consistency and completeness of the data submitted by MS have gradually improved over the
years in parallel with the development of national vigilance systems supported by the Vigilance Expert
Subgroup (VES). In addition, tissues and cells have been categorised into three groups (replacement,
haematopoietic stem cells (HSC) and reproductive) with the aim of improving reporting and in line with
the recommendations of the EU co-funded project Harmonising Activity Data Collection Exercises in
the Field of Tissues and Cells in Europe, 2018. 2
This report is the result of the joint efforts of and collaboration between healthcare professionals,
NCAs, the VES, the EDQM and the Commission. It summarises SARE data for 2021 submitted by 26 MS
plus Iceland, Liechtenstein, Norway and the United Kingdom (Northern Ireland). The report highlights
the main findings, conclusions and trends in the use of tissues and cells in humans across Europe in
terms of SARE occurrence and distribution (by category and type).
2 EXECUTIVE SUMMARY
The key findings of the 2021 reporting exercise are listed below:
• More than 3 million units of tissues and cells were processed by 25 countries (3 159 362), of
which 373 486 were replacement tissues and cells (reported by 22 countries), 57 941 were
HSC (reported by 18 countries) and 2 727 935 were reproductive tissues and cells (reported
by 18 countries). This is a 19.39% percent increase compared to 2020.
• More than 1 million units of tissues and cells were distributed (1 192 203) for application,
representing a 6.7% increase compared to 2020, of which 761 919 were reproductive tissues
and cells (reported by 21 countries), 391 687 were replacement tissues and cells (reported
by 27 countries) and 38 597 were HSC (reported by 21 countries).
• 318 467 recipients underwent transplant/infusion, which represents a 30% increase
compared to 2020.
1
Article 7 and Annexes III, IV and V of Directive 2006/86/EC
2
https://www.edqm.eu/documents/52006/162284/tissues-and-cells-conclusions-and-recommendations-harmonising-activity- data-
collection-exercises.pdf/b53fa49e-180e-c4ec-daaf-648f087da606?t=1629883980927
5
• Nineteen countries reported a total of 326 SAR in recipients, of which 55% were related to
reproductive tissues and cells, 27% to HSC and 18% to replacement tissues and cells:
o 70% of the SAR associated with reproductive tissues and cells were due to the
transmission of genetic conditions
o 40% of the 87 SAR associated with HSC resulted in graft failure or delayed function
and 19% were classified as immunological reactions
o 81% of the SAR associated with replacement tissues and cells were unclassified
(Other), while transmitted infections accounted for 19%
• An imputability level was not assigned for 65% of the reported SAR in 2021. In most cases,
conclusive evidence for attributing the adverse reactions to the quality/safety of tissues and
cells was not available and, as a result, imputability level 1 was assigned. This was also the
case for several fatalities following infusion of HSC; the clinical condition of patients was
assessed as playing the predominant role in the outcome.
• In 2021, 20 deaths of recipients were reported (significantly more than the 14 reported in
2020), of which 16 were potentially attributed to HSC and four to reproductive tissues and
cells.
• A total of 694 SAE were reported in 2021 (compared to 910 in 2020). This decrease is due to
the UK, a significant contributor throughout the years, no longer participating in SARE
reporting as a whole in 2021 subsequent to its withdrawal from the EU. As a result, Northern
Ireland was the only part of the UK to contribute to the exercise. Out of the 694 SAE, 170
were related to replacement tissues and cells (reported by 11 countries), 291 to HSC (18
countries) and 233 to reproductive tissues and cells (16 countries).
o In terms of the type of SAE, tissues or cells defect was the most commonly reported
event (40%), followed by system failure (21%) and human error (17%); the number
of events attributable to human error or Other events reported was lower than in
2020. Tissues or cells defect was the most frequent type of SAE associated with
replacement tissues and cells and HSC, while human error was the most frequent
type of SAE associated with reproductive tissues and cells.
o In terms of activity steps, SAEs for replacement tissues and cells most frequently
occurred or were identified during Other activity steps, followed by testing and
processing; events that involved HSC occurred or were identified during
procurement, processing and testing, while the most reported SAE for reproductive
tissues and cells were attributed to processing and donor selection, similar to the
previous year.
• 795 SAR in donors were reported on a voluntary basis by 17 countries, the vast majority (90%)
of which related to the donation of reproductive tissues and cells, all following donation of
oocytes. The most frequent types of SAR in oocyte donors were ovarian hyperstimulation
syndrome (OHSS) and surgical complications, while the remaining cases included transmitted
infections, ovarian torsion, and other. No instances of death in living donors of tissues and
cells were reported.
6
3 DATA COLLECTION AND ANALYSIS
The Commission provided the following tools to the participating NCAs to promote a standardised
approach to data reporting:
• A new electronic reporting form (online form, 2022 version)
It should be noted that this new form categorises tissues and cells into three groups
(replacement, HSC and reproductive), as opposed to just two in the past. The online form is
stored in the DG SANTE Data Collection Platform, with access to authorised users only.
• The Common Approach document (2022 version), which complements the electronic
reporting form and provides updated user instructions for data compilation.
The VES subgroup for SARE reporting improvement provided technical assistance with reporting for the
2022 SARE exercise and helped the Commission to test the online forms. Overall, the 2022 SARE
exercise ran smoothly with only minor issues to be considered for the 2023 exercise.
For the purpose of this year’s report, data analysis was performed for the three categories of tissues
and cells as set out in the new online form and the report structure was updated accordingly.
Both the reporting countries and the Commission verified the accuracy of the EDQM’s analysis and
interpretation of SARE data for 2021.
4 MAJOR FINDINGS
Activity data (denominators)
As part of the EU SARE exercise, MS are requested to provide data on not only SAR and SAE, but also
national tissue and cell activity. Although not legally binding, having access to data on the number of
tissues distributed, the number of recipients and the number of tissues processed at national level
helps to provide a better overview and understanding of the different activities within MS, with the
data also being used to give context to the SARE data.
In this exercise, as stated in the Common Approach, the number of tissues and cells distributed and
the number of recipients were used as denominators in the analysis of the SAR, while the number of
tissues processed was used as a denominator in the analysis of the SAE.
As in previous exercises, some countries had difficulty collecting complete and accurate activity data
for certain types of tissues and cells or certain activities, while others could not provide data as the
measurement units used at national level were not the same as those requested in the EU exercise
(e.g. in the field of medically assisted reproduction (MAR), some countries collected data as numbers
of cycles). Hence, SAR denominators might not be complete, and caution should be used when
interpreting them and deriving conclusions from this exercise.
4.1.1 Tissues and cells distributed
The total number of tissues and cells distributed in 2021 as submitted by the reporting countries was
1 192 203 units, comprising 391 687 units of replacement tissues and cells, 38 597 units of HSC and
761 919 units of reproductive tissues and cells.
7
4.1.1.1 Replacement tissues and cells
In the case of replacement tissues and cells, 24 countries reported data on units distributed (AT, BE,
BG, HR, CZ, DK, EE, FI, FR, DE, EL, HU, IE, IT, LT, LU, NL, NO, PL, PT, SI, ES, SE and UK). The main types of
replacement tissues and cells distributed were skeletal tissues (311 673 units) and ocular tissues (30
858 units). See Figure 1 for more details.
Skin (20,413) Other tissues or cells (22,313)
5% 6%
Cardiovascular tissues (6,430)
2%
Ocular tissues (30,858)
8%
Skeletal tissues (311,673)
79%
Figure 1. Total number of replacement tissues and cells distributed (units); data 2021
The sub-classification of the activity data by type of tissue for the main categories is shown in Figure 2
for skeletal tissues, Figure 3 for ocular tissues, Figure 4 for cardiovascular tissues and Figure 5 for other
replacement tissues. Bones, corneas and blood vessels were the most frequently distributed tissues in
each respective category.
Bone 263,439
General skeletal tissues 28,635
Tendons/ligaments 6,203
Fascia 5,925
Other (e.g. meniscus, ear, ossicles) 3,883
Cartilage 3,588
0 50,000 100,000 150,000 200,000 250,000 300,000
Figure 2. Number of skeletal tissues distributed per subcategory (units); 3 data 2021
3
The “general” category is used by MS that do not collect data separately for each subcategory of tissue or cells in some categories (e.g.
musculoskeletal tissues vs bone, cartilage, tendons/ligaments and other musculoskeletal tissues such as meniscus or ear ossicles).
8
Cornea 26,352
Sclera 2,553
General ocular tissue 1,953
Other 0
0 5,000 10,000 15,000 20,000 25,000 30,000
Figure 3. Number of ocular tissues distributed per subcategory (units); data 2021
Vessel 4,444
Heart valve 1,508
Other CV tissues
362
(e.g. conduit, patch or pericardium)
General CV 116
0 500 1,000 1,500 2,000 2,500 3,000 3,500 4,000 4,500 5,000
Figure 4. Number of cardiovascular tissues distributed per subcategory (units); data 2021
Amniotic membrane 16,908
Other (e.g. adipose tissue, tympanic membrane ) 4,157
Pancreatic islets 1,248
Hepatocytes 0
0 4,000 8,000 12,000 16,000 20,000
Figure 5: Other replacement tissues distributed per subcategory (units); data 2021
4.1.1.2 Haematopoietic stem cells
Seventeen countries reported data on distributed HSC (AT, BE, BG, DK, HR, CZ, EE, FI, EL, IE, IT, NL, PL,
PT, RO, SI and SE). Out of 38 597 units HSC reported as distributed, the majority (27 374 units) were
represented by peripheral blood stem cells (PBST), followed by general haematopoietic progenitor
cells (HPC, 4 347 units) and cord blood (2 604 units). See Figure 6 for more details.
9
Bone Marrow (1,846)
Other HSC (559) 5% Donor Lymphocyte Infusions (1,867)
1% 5%
Cord Blood (2,604)
7%
General HPC (4,347)
11%
Peripheral Blood Stem
Cells (27,374)
71%
Figure 6. Total number of hematopoietic stem cell units distributed (absolute values and percentage);
data 2021
Data on subcategories of HSC is presented in Figures 7-11 below.
Autologous 12,194
General 10,721
Allogenic unrelated 2,789
Allogenic related 1,670
0 2,000 4,000 6,000 8,000 10,000 12,000 14,000
Figure 7. Number of peripheral stem cell units distributed by type; data 2021
0 200 400 600 800 1,000 1,200 1,400
Autologous 35
Allogenic unrelated 226
Allogenic related 380
General 1,206
Figure 8. Number of bone marrow units distributed by type; data 2021
10
0 500 1,000 1,500 2,000 2,500 3,000
Autologous 1
Allogenic related 5
Allogenic unrelated 75
General 2,523
Figure 9. Number of cord blood units distributed by type; data 2021
General 1,089
Allogenic unrelated 418
Allogenic related 360
0 200 400 600 800 1,000 1,200
Figure 10. Number of donor lymphocyte infusion units distributed by type; data 2021
0 50 100 150 200 250 300 350 400 450 500
Autologous 0
Allogenic related 0
Allogenic unrelated 95
General 464
Figure 11. Number of other HSC unit distributed by type; data 2021
4.1.1.3 Reproductive tissues and cells
Twenty-one countries (AT, BE, BG, HR, CZ, DE, DK, FI, HU, IE, LI, LT, LU, LV, MT, NL, NO, PT, RO, SI and
SE) reported activity data for reproductive tissues and cells.
Of the 761 919 units of reproductive tissues distributed, 234 661 sperm units were delivered for
insemination (Figure 12) and 524 610 embryos were delivered for transfer following partner and non-
partner donation (Figure 13). In addition, 183 ovarian tissues and 2 465 testicular tissues were
distributed for the treatment of infertility (Figure 14).
11
Sperm non-partner
donation (30,401)
13%
Sperm partner
Sperm general (149,079) donation (55,181)
64% 23%
Figure 12. Number of sperm units distributed by category (absolute values and percentage); data 2021
Embryo donor oocyte, Embryo donor sperm and
partner sperm (24,710) oocyte (33,270)
5% 6%
Embryo donor sperm,
partner oocyte (8,082)
2%
Embryo general (275,496) Embryo partner
52% gametes (183,052)
35%
Figure 13. Number of embryos distributed by category (absolute values and percentage); data 2021
Testicular tissue (2,465) Ovarian tissue (183)
0% 0%
Sperm (234,661)
31%
Embryo (524,610)
69%
Figure 14. Total number of reproductive tissues distributed (units); data 2021
12
4.1.1.4 Incidence of replacement tissues and cells (per million population)
Taking into account the demographic data of the reporting countries on 1 January 2021,4 the incidence
of replacement tissues and cells, HSC and reproductive tissues and cells, presented comparatively by
distributed units and number of recipients (per million population), is shown in Figures 15, 16 and 17.
It should be noted that incidence was calculated only for those countries that reported distribution
data and/or number of recipients.
-400 100 600 1100 1600 2100 2600 3100 3600 4100
Austria (AT) 109
979
Bulgaria (BG)
83
106
Croatia (HR)
138
169
Czechia (CZ) 16
856
Denmark (DK)
409
568
Estonia (EE)
251
468
Finland (FI)
320
656
France (FR) 1137
1534
Greece (EL) 845
1409
Hungary (HU)
110
79
Ireland (IE)
143
146
Lithuania (LT)
57
58
Malta (MT)
12
12
Netherlands (NL) 429
4057
Norway (NO)
170
187
Poland (PL) 36
622
Portugal (PT)
129
115
Romania (RO)
7
7
Slovenia (SI)
109
176
Spain (ES)
503
669
Sweden (SE)
200
192
United Kingdom (UK)*
27
28
Incidence by Recipients pmp Incidence by Distributed T&C pmp
Figure 15. Incidence of replacement tissue and cell units (number of units distributed and number of
recipients per million population); data 2021
* https://www.nisra.gov.uk/publications/census-2021-table-lookups
4
https://ec.europa.eu/eurostat/web/population-demography/demography-population-stock-balance/database
13
-20 30 80 130 180 230 280 330
Austria (AT) 126
219
Bulgaria (BG) 22
23
Croatia (HR) 68
164
Czechia (CZ) 82
141
Denmark (DK) 88
209
Finland (FI)
88
95
France (FR) 79
Greece (EL) 50
50
Hungary (HU) 31
39
Ireland (IE) 149
165
Italy (IT) 80
92
Lithuania (LT) 81
81
Netherlands (NL) 102
325
Poland (PL) 20
254
Portugal (PT) 52
54
Romania (RO) 15
19
Slovenia (SI) 65
301
Spain (ES) 76
77
Sweden (SE) 86
106
United Kingdom (UK) 74
Incidence by Recipients pmp Incidence by Distributed T&C pmp
Figure 16. Incidence of haematopoietic stem cells (number of units distributed and number of recipients
per million population); data 2021
14
-900 100 1,100 2,100 3,100 4,100 5,100 6,100 7,100 8,100 9,100
Austria (AT) 1,212
2309
Bulgaria (BG) 1,334
9032
Croatia (HR) 1,423
2566
Czechia (CZ) 3,380
8696
Denmark (DK) 3,049
1131
Finland (FI) 1,247
Hungary (HU) 94
1032
Ireland (IE) 1,460
2191
Lithuania (LT)
763
763
Luxembourg (LU) 1,574
3099
Malta (MT)
595
595
Netherlands (NL) 1,778
3863
Portugal (PT)
656
529
Romania (RO)
536
536
Slovenia (SI) 2,377
3522
Sweden (SE) 1,165
1996
Incidence by Recipients pmp Incidence by Distributed T&C pmp
Figure 17. Incidence of reproductive cells (number of units distributed and number of recipients per
million population); data 2021
15
4.1.2 Number of transplant recipients
In 2021, 24 countries reported a total of 318 467 recipients having undergone a transplant of tissues
or cells (132 176 recipients of replacement tissue and cells, 23 423 recipients of HSC and 162 868
recipients were subjected to a MAR procedure).
4.1.2.1 Non-reproductive tissues and cells
As regards non-reproductive tissues and cells, 22 countries reported data on recipients (AT, BG, HR,
CZ, DK, EE, FI, FR, EL, IE, IT, LT, MT, NL, NO, PL, PT, RO, SI, ES, SE and UK).
Figures 18 and 19 show the total number of patients reported as having received each type of
non-reproductive tissue or cells: the most frequently transplanted were skeletal tissue, peripheral
blood stem cells and ocular tissues.
Cardiovascular Skin (485)
tissues (3,737) 0%
Ocular tissues (17,916) 3% Other tissues or cells (7,288)
14% 5%
Skeletal tissues (102,750)
78%
Figure 18. Total number of recipients per type of replacement tissue and cells; data 2021
Other Haematopoietic
Stem Cells (107) Bone Marrow (1,439)
0% 6% Donor Lymphocyte Infusions (1,234)
5%
Cord Blood (180)
1%
General HPC (4,150)
18%
Peripheral Blood Stem Cells (16,313)
70%
Figure 19. Total number of recipients per type of hematopoietic stem cells; data 2021
4.1.1.2 Reproductive tissues and cells
Concerning reproductive cells, only 16 countries (AT, BG, HR, CZ, DK, HU, FI, IE, LT, LU, MT, NL, PT, RO,
SI and SE) reported data indicating that 162 868 patients underwent a MAR procedure. Of those,
111 364 involved partner or non-partner embryos (68%), 51 163 involved partner or non-partner
sperm (32%), and less than 1% involved transplantation of testicular tissue (318 patients) or ovarian
tissue (23 patients) (Figure 20).
16
Testicular tissue (318) Ovarian tissue (23)
0% 0%
Sperm (51,163)
32%
Embryo (111,364)
68%
Figure 20. Total number of recipients per type of reproductive tissue and cells; data 2021
4.1.3 Trends in the distribution and application of tissues and cells
An overview of the data for the SAR denominators (number of tissues and cells distributed and number
of recipients) provided by the reporting countries for non-reproductive and reproductive tissues and
cells in the period 2012-2021 (data pertaining to 2011-2021) is presented in Figures 21 and 22,
respectively.
It should be noted that the total number of tissues and cells distributed (non-reproductive and
reproductive) in 2021 increased by almost 11% compared to the previous year. This is due to the
substantially increased contribution from the Netherlands (400% increase from 19 069 to 76 589),
Germany and France, which compensated for the UK ceasing reporting as a whole and for very low
reporting by Italy. This situation is different for transplant recipients: countries that reported data on
distribution did not necessarily report, or only partially reported, on transplantation (e.g. Belgium,
France, Germany, Italy, Poland); this was because the data were not collected in their country, the data
were not available at the time of reporting or for a different reason (e.g. more than one organisation
was responsible for a given country and only their data were reported). We acknowledge not only the
continued contribution, but also improvement in the reporting of the number of transplant recipients
by Spain, France, Greece, Norway and Poland. Finally, it can be assumed that the impact of the COVID-
19 pandemic on healthcare systems was less in 2021 compared to the previous two years.
For reproductive tissues and cells, the slight increase in both the number of units distributed (about
10%) and number of recipients (about 15%) of MAR procedures compared to 2020 is due to a
significant increase in reporting by several countries (Bulgaria, Norway, Germany, Belgium and the
Netherlands).
17
600,000
528,061 523,763
501,103
500,000
430,284
395,294
400,000 378,237
345,817
330,450 322,389 330,128
300,000 262,455
233,377
200,000
145,261 155,599
134,242
109,312 114,646 111,811
87,404 94,323
100,000 76,940 67,046
0
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Number Distributed Number Recipients
Figure 21. Total number of non-reproductive tissues and cells distributed (units) and number of
recipients of human tissues and cells: 2011-2021 comparative data
1,900,000 1,787,524
1,779,943
1,700,000
1,500,000
1,300,000
1,100,000
966,690
900,000 835,060
786,451 761,919
738,282
670,565
700,000 596,244
477,684 494,304
500,000
245,849 255,748 223,647 216,157 228,771
300,000 187,511
142,197 162,868
114,568 100,598 110,816
100,000
-100,000 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Number Distributed Number Recipients
Figure 22. Total number of reproductive tissues and cells distributed (units) and number of recipients
of human tissues and cells: 2011-2021 comparative data 5
4.1.4 Number of tissues and cells processed
Twenty-five countries (AT, BE, BG, HR, CZ, DK, EE, FI, DE, EL, HU, IE, IT, LU, LV, , MT, NL, NO, PL, PT, RO,
SI, ES, SE and UK) provided the number of non-reproductive tissues and cells processed, and 18
countries (AT, BG, BE, HR, CZ, DK, DE, HU, IE, LI, LV, LU, MT, NL, PT, RO, SI and SE) provided the number
of reproductive tissues and cells processed in 2021.
5
As stated in the Common Approach this data includes the number of sperm delivered to a clinic for insemination or to a laboratory for IVF,
the number of oocytes delivered to a laboratory for IVF and the number of embryos delivered to a clinic for transfer to patients.
18
As per the Common Approach, the term tissues and cells processed refers to tissues and cells
processed in tissue establishments (TEs), but not necessarily distributed to end users. A total of 3 159
362 tissues and cells were reported as processed in 2021, 29% more than in 2020 (2 647 079). Of those,
373 486 units (12%) were replacement tissues and cells, 57 941 units (2%) were HSC and 2 727 935
units (86%) were reproductive tissues and cells. Comparative data from previous exercises (2011-2021
data) is presented in Figure 23.
3,500,000
3,159,362
2,922,117
3,000,000
2,584,557
2,443,564
2,500,000 2,280,512
2,000,000 1,862,293
1,775,082
1,550,701
1,433,828
1,500,000
887,536
1,000,000 748,753
500,000
0
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Figure 23. Total number of tissues and cells processed (units): 2011-2021 comparative data
Serious adverse reactions in recipients
A total of 326 SAR were reported in 2021, a 7% decrease compared to 2020 (350). Of these, 58 (18%)
were related to replacement tissues and cells, 87 (27%) to HSC and 181 (55%) to reproductive tissues
and cells.
In 2021, 19 SAR related to the transplantation of HSC (15) and reproductive cells (4) were associated
with fatalities. In all but one case, the imputability level assigned was possible (level 1) or
likely/probable (level 2). While imputability due to graft failure cannot be excluded, the patient’s
underlying condition was a major factor in the outcome of these cases.
A comparison of the number of SAR reported by countries between 2011-2021 for both categories
(non-reproductive and reproductive tissues and cells) is presented in Figure 24. In general, there has
been an increasing trend in SAR reported for reproductive tissues and cells, while the number of SAR
reported for non-reproductive tissues and cells has remained relatively constant.
19
350
300
250 211 181
150
200
79 172 124 131 142
150 15 81
29
100
141 156 139 145
50 109 124 109 97 101 90
74
0
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Non-reproductive Tissues & Cells Reproductive Tissues & Cells
Figure 24. Non-reproductive versus reproductive tissues and cells SAR: 2011-2021 comparative data
4.2.1 General information
Of the 29 reporting countries, 19 (AT, BE, CZ, DK, EE, FI, FR, DE, EL, IE, IT, HR, NL, PT, PL, ES, SE, NO and
UK) reported SAR associated with the clinical application of tissues or cells. Nine EU MS (BG, HU, LU,
LV, LT, MT, RO, SK and SI) reported no SAR in recipients in 2021. A graphical representation of the
number of SAR in transplant recipients by country in 2021 is available in Figure 25.
70 64
60
53 53
50
31
30 24
23
20 17
14
10 7 7
0
Figure 25. Total number of SAR by country in transplant recipients; data 2021
Ten countries (BE, DK, FR, DE, EL, IE, IT, NL, PT and ES) reported SAR associated with the transplantation
of replacement tissues and cells, nine (AT, BE, FR, DE, EL, IE, NL, PL and ES) reported SAR associated
with the transplantation of HSC, and 13 (BE, HR, CZ, DK, EE, FI, IE, IT, NO, PT, ES, SE and UK) reported
SAR following the clinical application of reproductive tissues or cells.
The frequency of SAR was assessed by calculating the incidence in relation to the number of tissues
and cells transplant/application procedures. SAR from countries that did not report the number of
recipients were not considered.
20
SAR incidence was calculated per 10 000 transplant recipients (based on data provided by seven
countries for replacement tissues and cells, seven countries for HSC and five countries for reproductive
tissues and cells). It varies largely from country to country and is significantly higher for HSC (Tables 1-
3).
Incidence of SAR /
Country Number of recipients Number of SAR
10 000 recipients
Denmark (DK) 685 2 29
France (FR) 10 738 18 17
Greece (EL) 328 3 91
Ireland (IE) 46 1 217
Netherlands (NL) 1 591 1 6
Portugal (PT) 931 1 11
Spain (ES) 23 753 11 5
Table 1. Number of SAR per 10 000 recipients of replacement tissues and cells; data 2021
Incidence of SAR /
Country Number of recipients Number of SAR
10 000 recipients
Austria (AT) 329 3 91
France (FR) 4 971 46 92
Greece (EL) 358 14 391
Ireland (IE) 676 2 29
Netherlands (NL) 30 1 333
Poland (PL) 747 7 94
Spain (ES) 3 620 4 11
Table 2. Number of SAR per 10 000 recipients of haematopoietic stem cells; data 2021
Incidence of SAR /
Country Number of recipients Number of SAR
10 000 recipients
Croatia (HR) 5 744 5 9
Czechia (CZ) 29 064 14 5
Denmark (DK) 4 511 29 64
Ireland (IE) 321 3 93
Portugal (PT) 3205 6 19
Table 3. Number of SAR per 10 000 recipients of reproductive cells; data 2021
These data should be interpreted with caution, as they may not reflect the improvement/deterioration
of quality and safety measures but rather the increased effectiveness and completeness of the national
vigilance and reporting systems – higher incidence may be an indication of more effective detection
and reporting systems rather than an actual increase in the number of SAR.
21
4.2.2 SAR by category of tissues and cells
In total, 55% of the 326 SAR in recipients reported were associated with the application of reproductive
tissues and cells, compared to 27% associated with the transplantation of HSC and 18% for
replacement tissues and cells (Figure 26).
Replacement T&C (58)
18%
Hematopoietic Stem
Cells (87)
Reproductive T&C (181) 27%
55%
Figure 26. Number of SAR by category of tissue and cells; data 2021
The distribution of SAR per reporting country and category of tissue and cells is presented in Figure 27.
SAR per country and category of T&C
0 10 20 30 40 50 60 70
Austria (AT) 3
Belgium (BE) 2 5 7
Croatia (HR) 5
Czechia (CZ) 53
Denmark (DK) 2 29
Estonia (EE) 1
Finland (FI) 5
France (FR) 18 46
Germany (DE) 18 5
Greece (EL) 3 14
Ireland (IE) 12 3
Italy (IT) 11
Netherlands (NL) 11
Norway (NO) 24
Poland (PL) 7
Portugal (PT) 1 6
Spain (ES) 11 4 38
Sweden (SE) 4
United Kingdom (UK) 5
Replacement TC Haematopoietic TC Reproductive TC
Figure 27. Number of SAR per country and category of tissues and cells; data 2021
22
A breakdown of SAR by subcategory of tissues and cells is presented in Figures 28-30.
Other tissues or cells (11)
19%
Skeletal tissues (15)
26%
Skin (1)
2%
Cardiovascular tissues (3)
5%
Ocular Tissues (28)
48%
Figure 28. Number of SAR per subcategory of replacement tissues and cells (absolute values and
percentages of total SAR in recipients); data 2021
Out of the 58 SAR associated with transplant of replacement tissues and cells, the most frequent were
for ocular tissues (48%), specifically corneal tissue. As regards skeletal tissues, the largest number of
reactions was associated with bones (10), with two cases each for cartilage and tendons and ligaments.
The number of SAR for each subtype of replacement tissues and cells is presented in Table 4.
Replacement Tissues and cells Number of
tissues and cells subtype SAR
Skeletal tissues Bone 10
Tendons/ligaments 2
Cartilage 2
General skeletal tissues 1
Ocular tissues Cornea 28
Cardiovascular tissues Heart valve 1
Vessel 2
Skin Skin 1
Other tissues or cells Amniotic membrane 11
Table 4. Number of SAR by subtype of replacement tissues and cells; data 2021
23
Cord blood (3)
3% General HPC (4)
5%
Bone marrow (auto+allo) (19)
22%
Peripheral blood progenitor
cells (auto+allo) (61)
70%
Figure 29. Number of SAR per subcategory of haematopoietic stem cells (absolute values and
percentage of total SAR in recipients); data 2021
The HSC subcategory most frequently associated with severe adverse reactions was the transplant of
allogenic related peripheral blood progenitor cells. Details for all types and subtypes of HSC are
presented in Table 5.
HSC HSC subtype Number
of SAR
Bone marrow Allogenic related 8
Allogenic unrelated 5
General 6
Cord blood Allogenic related 3
Peripheral blood progenitor cells Allogenic related 10
Allogenic unrelated 31
Autologous 7
General 13
General HPC 4
Table 5. Number of SAR by subtype of haematopoietic stem cells; data 2021
24
MAR procedures involving embryos were responsible for 66% of SAR in 2021, followed by sperm
insemination as shown in Figure 30.
Ovarian tissue (0)
0%
Sperm (62)
34%
Embryo (119)
66%
Figure 30. Number of SAR per subcategory of reproductive cells (absolute values and percentages of
total SAR in recipients); data 2021
SAR for sperm used in both IUI procedures and embryos after IVF/ICSI were reported; the number for
each subtype of tissues and cells involved is presented in Table 6.
Reproductive tissues and cells Tissues and cells subtype Number of
SAR
EMBRYO Donor oocyte, partner sperm 50
Donor sperm and oocyte 15
Donor sperm, partner oocyte 17
Partner gametes 29
General 8
SPERM Non-partner donation 56
Partner donation 6
Table 6. Number of SAR by subtype of reproductive tissues and cells; data 2021
4.2.3 SAR by type of reaction
Major categories of reactions following application of replacement tissues and cells and HSC listed in
the Common Approach include transmitted infections (bacterial, viral, parasitical, fungal, prion
disease, other transmitted infections), transmitted malignant diseases, other disease transmission
(immunological, genetic, other donor derived disease) and Other SAR (cardiovascular reaction,
pulmonary reaction, neurological reaction, toxicity, immunological reactions, graft failure/delayed
engraftment, etc.).
25
4.2.3.1 SAR – replacement tissues and cells
0 5 10 15 20 25
Bacterial (5)
Viral other (2) 2
Fungal (4) 4
Immunological
reactions (3)
Graft failure/
delayed (28) 14 12 1 1
Undue exposure to
risk interventions (3) 1 1 1
Others (13) 2 11
Skeletal tissues Ocular Tissues Cardiovascular Tissues Skin Other tissues or cells
Figure 31. Distribution of SAR for replacement tissues and cells per type of reaction; data 2021
Details on the breakdown of SAR by type of reaction for replacement tissues and cells are provided
below:
1. Transmitted infections were reported in 11 patients, representing 19% of all reported SAR
for replacement tissues and cells. Ten cases of bacterial (Enterococcus faecium,
sclerokeratitis), viral (herpes infection, herpetic uveitis) and fungal infections (Candida
albicans, Candida glabrata) were associated with the corneal transplants and one reaction
was reported in connection with a cryopreserved vascular graft.
2. Other SAR: of the 47 SAR reported (representing 81% of all reported SAR for replacement
tissues and cells), the largest specified subcategory was related to graft function failure,
followed by undue exposure to risk intervention; the number of reactions not classified
decreased from 48 in 2020 to 13 in 2021.
o 28 cases of graft failure or delayed engraftment, as follows:
14 following the transplantation of skeletal tissue (10 related to bones, two
to cartilage and two to tendons and ligaments)
one following the transplantation of cardiovascular tissue (vessel)
12 following the transplantation of ocular tissue (all corneas)
one following transplantation of skin
o Three cases of undue exposure to risk interventions (e.g. patient under anaesthesia
without a suitable graft available and surgery postponed or rescheduled, incorrect
graft size):
one following cardiovascular tissue transplantation (heart valve)
one ocular tissues (cornea)
one general skeletal tissue
o Three cases of immunological reactions (graft failure) following transplantation of
ocular tissues (corneas)
26
o 13 SAR were classified as Other, including 11 cases of corneal pannus related to the
application of amniotic membrane and two SAR that occurred following the
transplantation of ocular tissue (post-graft corneal striae and corneal oedema).
4.2.3.2 SAR – haematopoietic stem cells
The second most prevalent of all SAR reported in 2021 were those associated with transplant of HSC
(87). Apart from one case of fungal infection and one of other disease transmission (immunological
disease), the remaining 85 SAR were reported as Other SAR. No instances of malignant disease were
reported. The types of reaction encountered in 2021 are presented in Figure 32.
0 5 10 15 20 25 30 35
Fungal Infection (1) 1
Cardiovascular reactions (1) 1
Pulmonary reactions (4) 1 3
Neurological reactions (3) 3
Toxicity (3) 2 1
Immunological reactions (17) 2 11
Graft failure/delayed (35) 12 22 1
Infusion related
non specific symptoms (7) 1 6
Other (15) 2 12 1
Immunological disease (1) 1
General HPC Bone marrow Peripheral blood progenitor cells Cord blood
Figure 32. Distribution of SAR for haematopoietic stem cells by type of reaction; data 2021
The breakdown of SAR by type of reaction for replacement tissues and cells is provided in Table 7
below:
1. Transmitted infections: One instance of fungal infection caused by Candida glabrata in a
patient that had undergone a transplant of peripheral blood stem cells (PBSC).
2. Other SAR:
o 35 cases of graft failure or delayed engraftment following transplantation of bone
marrow (three allogenic related, three allogenic unrelated and three general), cord
blood (1 allogenic unrelated) and PBSC (four allogenic related, 11 allogenic unrelated,
one autologous and three general)
o 17 cases of immunological reactions following transplantation of bone marrow (two
allogenic related, one allogenic unrelated and one general), HSC (two general), and
PBSC (four allogenic related, six allogenic unrelated, and one autologous)
o seven cases of infusion related non-specific symptoms following transplantation of
bone marrow (one general), and PBSC (one allogenic unrelated, two autologous and
three general)
27
o 15 SAR were classified as Others and occurred following transplantation of bone
marrow (one autologous unrelated and one general), cord blood (one autologous
unrelated), HSC (one general), and PBSC (one allogenic related, three allogenic
unrelated, one autologous and six general)
o four cases of pulmonary reactions following transplantation of PBSC (three allogenic
unrelated and one autologous)
o three cases of neurological reactions following transplantation of PBSC (one allogenic
related and two allogenic unrelated)
o one case of cardiovascular reaction following transplantation of bone marrow
(allogenic related)
o three cases of toxicity following transplantation of cord blood (one allogenic
unrelated) and PBSC (one allogenic unrelated and one general)
3. Other disease transmission: one case of immunological reaction (anaphylactic shock)
following transplantation of allogenic unrelated PBSC.
HSC subtype
SAR type SAR subtype HSC type Allogenic Allogenic
Autologous General
related unrelated
Transmitted Fungal infection
PBSC (1) 1
infections (1) (Candida glabrata) (1)
Other disease Immunological reaction
PBSC (1) 1
transmission (1) (anaphylactic shock) (1)
Other SAR (85) Bone marrow (12) 6 3 3
Graft failure/delayed
engraftment (35) Cord blood (1) 1
PBSC (23) 4 14 1 3
Bone marrow (4) 2 1 1
Immunological reactions
General HSC (1)
(17)
PBSC (11) 4 6 1
Infusion related non- Bone marrow (1) 1
specific symptoms (7) PBSC (6) 1 2 3
General HSC (1)
Pulmonary reactions (4)
PBSC (3) 3
Neurological reactions (3) PBSC (3) 1 2
Cardiovascular reaction
Bone marrow (1) 1
(1)
Cord blood (1) 1
Toxicity (3)
PBSC (2) 1 1
Bone marrow (2) 1 1
Cord blood (1) 1
Others (15)
General HSC (1)
PBSC (11) 1 3 1 6
Table 7. Breakdown of SAR in HSC by type and by reaction and HSC subtype; data 2021
4.2.3.3 SAR – reproductive tissues and cells
Major categories of SAR associated with the application of reproductive tissues and cells listed in the
Common Approach include transmitted infections (bacterial, viral, parasitical, fungal, prion disease,
other transmitted infections), transmitted malignant diseases, transmitted genetic conditions and
Other SAR (cardiovascular reaction, pulmonary reaction, anaphylactic reaction, ectopic or molar
pregnancy, etc.).
28
Among the 181 SAR associated with the application of reproductive tissues and cells, 59% (107) were
classified as transmitted genetic conditions, and the rest were reported as Other SAR (61) and other
disease transmissions (13). The types of SAR per type of gametes (partner/non-partner), embryo
application and sperm application are presented in Figures 33 and 34 respectively.
1. Transmitted infection: no cases reported.
2. Transmitted malignant disease no cases reported.
3. Transmitted genetic conditions: 107 SAR were reported in this category and represent the
most common type related to reproductive tissues and cells (59%). These comprised:
o 46 cases involving embryos from donor oocytes and partner sperm, 14 cases of
embryos from donor sperm and oocytes,
o 14 cases of embryos from donor sperm and partner oocytes
o 24 cases of sperm from non-partner donation
o five cases related to embryos from partner gametes
o four cases concerning sperm in the general category
4. Other SAR: ectopic pregnancy was the most common of the 61 SAR categorised as Other,
representing 20% of all reported SAR for reproductive tissues and cells. Nine cases of donors
with germline mutations, one case of RASopathy and seven cases of anaphylactic reaction
were also included in this category. Of the SAR reported as Other:
o 24 cases occurred following clinical application of embryos from partner gametes
o four cases involved general embryos
o four cases involved embryos from donor oocytes and partner sperm
o three cases involved embryos from donor sperm and partner oocytes
o one case involved embryos from donor sperm and oocytes, 20 cases involved sperm
from non-partner donation
o six cases involved partner sperm
5. Other disease transmissions: the cases reported in this category include eight instances of
germline mutation, three cases of genetic diseases and one case of spina bifida.
0 10 20 30 40 50 60 70 80
Transmitted Genetic
Conditions (83) 46 14 14 5 4
Ectopic pregnancy (30) 313 23
Molar pregnancy (1) 1
Pregnancy of
unknown origin (1) 1
Bacterial infection
ovaries (3) 3
Pneumonia (1) 1
Donor oocyte, partner sperm Donor sperm and oocyte Donor sperm, partner oocyte
Partner gametes General Embryos
Figure 33. Distribution of SAR per type of gametes (partner/non-partner), embryo application; data
2021
29
0 5 10 15 20
Transmitted Genetic Conditions (24) 24
Ectopic pregnancy (7) 1
Other disease transmission (13) 13
Anaphylactic reaction (7)
Other SAR (11) 11
Sperm Non-partner donation (56) Sperm Partner donation (6)
Figure 34. Distribution of SAR per type of gametes (partner/non-partner), sperm application; data 2021
It should be noted that of the 181 SAR associated with the application of reproductive cells, 76% were
related to non-partner donation – 56 involved non-partner sperm, 50 involved embryos from donated
oocytes, 15 embryos from donated sperm and oocytes and 17 embryos from donated sperm (Table 8).
Reproductive Numbe
Tissues and cells subtype SAR %
tissues and cells r of SAR
EMBRYO Donor oocyte, partner sperm 50 28
Donor sperm and oocyte 15 8
Donor sperm, partner oocyte 17 9
Partner gametes 29 16
General 8 4
SPERM Non-partner donation 56 31
Partner donation 6 3
Table 8. SAR related to the application of non-partner gametes (absolute values and percentage); data
2021
4.2.3.4 SAR Imputability
The Common Approach (2022 version) requires that the imputability assessment tool provided be used
to determine which reactions must be reported for the purpose of this exercise. In 2021, an
imputability level was assigned to only 35% of the SAR reported (115 out of 326). As shown in Table 9
below, for most events, conclusive evidence for attributing the reaction to the quality or safety of the
tissue or cells (for recipients) or to the donation process (for donors) was not present. In most cases of
SAR in recipients of HSC infusions associated with fatalities, imputability was assessed as level 1
(possible) or level 2 (likely, probable) and the evidence supported the hypothesis of death due to the
clinical condition of the patients rather than a relationship to the tissue or cells.
The types of SAR to which imputability level 3 (definite/certain) was assigned included immunological
reactions (6), graft failure/delayed engraftment (3), transmitted fungal and bacterial infections (2 and
1, respectively), undue exposure to risk interventions (2), pulmonary reaction (1), immunological
disease (1) and transmitted genetic conditions in conjunction with MAR procedures (2).
30
Imputability reported Imputability level
Tissues and cells Total number of
category SAR in 2021 Number % IL1 IL2 IL3
Replacement
58 41 e12 27 7 7
tissues and cells
HSC 87 65 20 41 14 10
Reproductive
181 9 3 7 - 2
tissues and cells
Total 326 115 35 75 21 19
Table 9. SAR with imputability level reported per category of tissues and cells; data 2021
4.2.4 Deaths of recipients of tissues and cells
As vigilance systems are in place to protect donors and recipients, the Commission and MS deemed it
appropriate to regularly collect, on a voluntary basis, information on reported deaths.
Twenty deaths in recipients were reported in 2021: 16 were potentially attributable to HSC application
and four to reproductive tissue and cell application; 14 fatalities among recipients potentially
attributable to tissue and cell application were reported the previous year.
4.2.4.1 Deaths following the application of HSC
Detailed information on the eight reported deaths potentially attributable to HSC is provided below:
o one death after a second autologous peripheral blood stem cell transplant (PBSCT) due to
septic shock by bacterial translocation and significant immunosuppression (acute digestive
graft-versus-host disease and post-transplant infections); imputability to graft quality could
not be completely ruled out (previous clinical status of the patient was IgA lambda multiple
myeloma)
o one death after allogenic related bone marrow transplant due to cardiogenic shock
following myopericarditis
o one death after autologous PBSCT with unidentified cause
o one death after PBSC graft failure and thrombocytopenia complicated by cerebral
haemorrhage, possibly attributable to graft quality (low viability of cryopreserved CD34+
after thawing)
o one death allogenic PBSCT due to multiple organ failure; imputability to graft quality could
not be completely ruled out (previous clinical status of the patient was severe aplastic
anaemia and treatment with ATGAM/CsA/steroids; haemoculture result was negative and
donor and recipients were serologically compatible)
o three deaths after PBSCT or during the first hospitalisation associated with the transplant
4.2.4.2 Deaths following the application of reproductive tissues and cells
Details of the four reported MAR-related deaths (i.e. reproductive tissues and cells), which include
offspring and foetal deaths (at various stages of pregnancy), are listed below:
o three deaths related to IVF (death of offspring)
o one death related to partner sperm donation: oocyte donor detected as heterozygote carrier
(induced abortion due to diagnosis of spina bifida).
31
Serious adverse events
4.3.1 General information
The reported number of tissues processed was 16% higher in 2021 compared to 2020 (Figure 35); this
was due to the significant contribution of one country that did not report in previous years and a few
other countries whose reporting increased in 2021, thus compensating for the reduced reporting by
other countries. The total number of SAE reported was down 24% compared to the previous exercise
and 27% compared to 2019 (Figure 36). This does not necessarily signify a reduction in SAE reporting;
this could be a sign of mature quality systems and better understanding of SAE reporting.
Eleven countries reported SAE for replacement tissues and cells (AT, BE, FR, DE, HU, IT, MT, NL, PL, ES
and SE), 18 for HSC (AT, BE, BG, HR, CZ, FI, FR, DE, EL, IE, IT, NL, NO, PL, PT, ES, SE and UK) and 16 for
reproductive tissues and cells (BE, BG,HR, CZ, DK, EE, FI, FR, DE, IE, IT, LV, NL, PT, ES and SE). Fewer
countries reported SAE in 2021 than in 2020.
Of the 694 SAE reported for 2021, 42% were related to HSC, 34% to reproductive cells and tissues and
24% to replacement tissues and cells. The proportion is similar to the previous year (72% non-
reproductive tissue and cells and 28% reproductive tissues and cells).
3500000 949 1000
910
3,159,362
900
3000000 2,922,117
769 739
756 694 800
622 2,584,557
2,443,564
2500000 700
2,280,512
551 600
2000000 441 1,862,293
499
1,775,082
1,550,701 500
426
1,433,828
1500000
400
1000000 887,536 300
748,753
200
500000
100
0 0
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
YEAR Tissues Processed Number SAE
Figure 35. Number of tissues processed and number of SAE reported; 2011-2021 comparative data
The frequency of SAE was assessed by calculating its incidence in relation to the number of tissues and
cells processed. SAE from countries that did not report the number of processed tissues and cells were
not considered.
The incidence of SAE was calculated per 10 000 tissues and cells processed (based on data provided by
10 countries for replacement tissues and cells, 13 countries for HSC and 11 countries for reproductive
tissues and cells). Similar to SAR, the incidence of SAE varies largely from country to country and is
significantly higher for HSC (Tables 10-12).
32
Incidence of SAE /
Number of tissues Number
Country 10 000 tissues and
and cells processed of SAE
cells processed
Austria (AT) 66 786 5 0.75
Belgium (BE) 22 529 32 14.2
France (FR) 103 773 17 1.6
Germany (DE) 159 566 9 0.56
Hungary (HU) 1 226 55 9
Italy (IT) 8 996 10 11
Netherlands (NL) 12 670 6 5
Poland (PL) 46 367 1 0.2
Spain (ES) 29 251 27 9
Sweden (SE) 3 459 7 20
Table 10. Number of SAE per 10 000 replacement tissues and cells processed; data 2021
Incidence of SAE /
Number of HSC Number
Country 10 000 tissues and
processed of SAE
cells processed
Austria (AT) 2 856 3 10
Belgium (BE) 3 134 17 54
Bulgaria (BG) 774 3 39
Croatia (HR) 1 602 3 19
Czechia (CZ) 2 209 2 9
Finland (FI) 1 018 5 49
Ireland (IE) 434 8 184
Italy (IT) 6 023 11 18
Netherlands (NL) 3 105 3 10
Poland (PL) 31 040 5 2
Portugal (PT) 711 34 478
Sweden (SE) 1 795 7 39
United Kingdom (UK) 131 1 76
Table 11. Number of SAE per 10 000 haematopoietic stem cells processed; data 2021
Incidence of SAE /
Number of tissues Number
Country 10 000 tissues and
and cells processed of SAE
cells processed
Belgium (BE) 462 323 33 0.7
Bulgaria (BG) 128 270 1 0
Croatia (HR) 51 507 2 0.4
Czechia (CZ) 377 585 6 0.2
Denmark (DK) 49 627 24 5
Germany (DE) 870 300 5 0
Ireland (IE) 102 932 3 0.3
Latvia (LV) 31 780 1 0.3
Netherlands (NL) 245 607 4 0.2
Portugal (PT) 10 686 8 7
Sweden (SE) 190 052 11 0.6
Table 12. Number of SAE per 10 000 reproductive tissues and cells processed; data 2021
33
4.3.2 SAE by type of event
The Common Approach includes six categories of SAE: tissues and cells defect, system failure,
equipment failure, materials, human error and Other.
Tissues and cells defect remained the leading category of events with 40% out of the total 694 SAE
that occurred in 2021, followed by system failure (21%). Figure 36 shows the positive evolution of
events reported as being related to human error (a decrease from 31% in 2019 to 20.8% in 2020 and
17% in 2021) and of those classified as Other (from 23% in 2019 to 23.4% in 2020 and 10% in 2021).
900
217
800 213
700 168 126
156 70
600 295 190
109 119
500 128
295 357 248 122
148 145
400 87 119
53 331 189 47 41
26 48
300 263 55 43
148 175 78 39
168 193
200 67
8 91 65 60 290 276
94 81 228 234 254
100 82
149 117 121
100 82 79
47
0
2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Tissue/cell defect Equipment failure Materials System failure Human error Other
Figure 36. Distribution of SAE by type/specification; 2010-2021 data
The distribution of SAE by type/specification for each of the three categories of tissues and cells is
presented in Figures 37-39.
Other (23)
14%
Human error (26)
15% Tissue or cell
defect (84)
50%
System failure (33)
19%
Materials (2) Equipment failure (2)
1% 1%
Figure 37. SAE types for replacement tissues and cells (absolute values and percentages); data 2021
34
Human error (14)
5% Other (33)
11%
System failure (39)
13%
Tissue or cell defect (162)
56%
Materials (24)
8%
Equipment failure (19)…
Figure 38. SAE types for haematopoietic tissues and cells (absolute values and percentage); data 2021
Other (14)
6%
Tissue or cell defect (30)
13%
Equipment failure (22)
10%
Human error (79) Materials (15)
34% 6%
System failure (73)
31%
Figure 39. SAE types for reproductive tissues and cells (absolute values and percentage); data 2021
35
4.3.3 SAE by activity step
Following the harmonisation of practices, two new activity steps – product selection and issue – were
added to the reporting template for 2019.
An overview of the SAE reported for each of the three categories of tissues and cells by activity step is
presented in Figures 40-42.
Other (62)
36% Donor selection (15)
9%
Transport (5)…
Procurement (12)
Distribution (7) 7%
4%
Issue (8) Testing (28)
5% 16%
Product selection (6)
4%
Storage (8)
5%
Processing (19)
11%
Figure 40. Distribution of SAE for replacement tissues and cells by activity step; data 2021
Storage (15)
5%
Product selection (8)
3%
Issue (4)
Distribution (5)
1%
Processing (100) 2%
Transport (7)
34% 2%
Other (12)
4%
Donor selection (15)
Testing (19) 5%
7%
Procurement (106)
37%
Figure 41. Distribution of SAE for haematopoietic stem cells by activity step; data 2021
36
Donor selection (30)
13%
Other (35) Procurement (11)
Transport (13) 15% 5%
5%
Testing (7)
Distribution (7) 3%
3%
Issue (7)
3%
Product selection (10) Processing (93)
4% Storage (20) 40%
9%
Figure 42. Distribution of SAE for reproductive tissues and cells by activity step; data 2021
The distribution of SAE by activity step differs among the three categories of tissues and cells. However,
SAE reported as occurring or being discovered during processing, procurement, donor selection and
testing are the most frequent for all categories of cells, and account for 59% of all SAE in 2021. An
overview of the SAE reported for each of the three categories of tissues and cells by activity step is
presented in Figures 43-45.
0 10 20 30 40 50 60
Donor selection 10 3 2
Procurement 5 5 2
Testing 2 11 6 18
Processing 11 11 3 3
Storage 6 11
Product selection 5 1
Issue 7 1
Distribution 1 3 1 2
Transport 3 2
Other 50 2 7 3
Tissue or cell defect Equipment failure Materials System failure Human error Other
Figure 43. Distribution of SAE for replacement tissues and cells by activity step and SAE type (absolute
values and percentages); data 2021
37
0 20 40 60 80 100
Donor selection 11 22
Procurement 78 23 14 2 7
Testing 3 3 13
Processing 58 8 10 15 4 5
Storage 7 5 3
Product selection 7 1
Issue 22
Distribution 3 11
Transport 3 121
Other 21112 5
Tissue or cell defect Equipment failure Materials System failure Human error Other
Figure 44. Distribution of SAE for haematopoietic stem cells by activity step and SAE type (absolute
values and percentages); data 2021
0 10 20 30 40 50 60 70 80 90 100
Donor selection 22 21 5
Procurement 4 5 2
Testing 5 11
Processing 1 12 5 30 40 5
Storage 6 3 3 7 1
Product selection 6 4
Issue 4 3
Distribution 5 2
Transport 1 4 1 3 3 1
Other 1 2 14 16 2
Tissue or cell defect Equipment failure Materials System failure Human error Other
Figure 45. Distribution of SAE for reproductive tissues and cells by activity step and SAE type (absolute
values and percentages); data 2021
For replacement tissues and cells, the largest number of reported SAE, after Other (62 / 36%), were
SAE that occurred during testing (28 / 16%), processing (19 / 11%) and donor selection (15 / 9%). 50
out of the 62 SAE reported as Other were identified as tissues and cells defects, two were system
failures, seven human errors and three unclassified (Other). Among the seven SAE in the human error
group, three were identified as human error - incorrect decision or omission following the correct
procedure, and four as Other: transplant of tissue after expiry date (2), splitting of tissue with risk of
losing traceability (1) and missing tissue with loss of traceability (1).
38
The three SAE reported as Other included positive microbiological test result of tissues culture prior to
implantation (bacterial contamination of skeletal tissue (1) and contamination of ocular tissue with
fungi (2)).
Out of the 28 SAE in relation to testing, 18 were reported as Other and included bacterial and fungal
contamination of pre-implant culture or transport medium of ocular tissue (cornea, scleral ring), along
with identification of gram-positive bacteria in exudate post-skeletal tissue (bone) implant. The six SAE
reported as human error – incorrect decision or omission following the correct procedure were due
to a failure to perform SARS COV-2 testing timely, resulting in the loss of ocular tissue.
In the HSC category, the top three activities in the transfusion cycle where SAE occurred or were
identified, were procurement (106 / 37%), processing (100 / 34%) and testing (19 / 7%). The most
prevalent events encountered throughout the transfusion cycle for HSC were represented by tissues
and cells defect, and within this type, by bacterial contamination. In the subgroup procurement, over
70% of SAE were cases of tissues and cells defect, followed by system failure (13) and Other (7); the
most frequent type of defect reported was bacterial contamination of HSC (57 SAE); eight of the system
failure SAE were positive test results for bacteria, and in the non-classified group of SAE, bacterial
contamination was the issue. The SAE related to processing were predominantly cases of tissues and
cells defect (58 cases), specifically insufficient cell count/low cell viability after thawing and bacterial
contamination of HSC. Materials and system failure contributed 10 SAE each to sub-groups of events
related to processing.
The SAE reported in relation to MAR procedures were of a different nature to those for the other two
categories of cells. Most events occurred or were identified during processing (93 / 40%), donor
selection (30 / 13%), while 35 SAE (15%) were unclassified (Other). Two-thirds of SAE during processing
were attributed to human error (40 out of 93) and system failure (30 out of 93), followed by
equipment failure (12 / 13%). In the donor selection group of SAE, tissues and cells defects were the
most frequent. Out of 35 unclassified SAE, 11 were attributed to system failure and 16 to other human
error.
Examples of SAE and the assigned specification for the three categories of tissue and cells are provided
in Annex 1. Note that the intent was to provide an illustration of SAE reported for the chosen activities,
not an exhaustive list. The concern is that the SAE specification was not always adequately assigned.
In addition, the description provided was not always clear, preventing understanding of the events
reported.
Serious adverse reactions in donors
Recognising the importance of all donor adverse reactions, including those not directly impacting the
quality and safety of tissues and cells and reported through pharmacovigilance systems (e.g. OHSS
following oocyte donation and reactions subsequent to the administration of granulocyte colony-
stimulating factor for the collection of PBSC), the Commission continues to collect such data on a
voluntary basis, in agreement with the NCAs.
Seventeen countries (BE, BG, HR, CZ, EE, FI, FR, DE, EL, IE, IT, NL, PL, PT, SI, ES and SE) reported a total
of 795 SAR in donors in 2021. An overview of SAR in donors during the period 2012-2022 (data
pertaining to 2011-2021) is presented in Figure 46.
39
1000 17 17
19
17
800 19 21
19 17
600 18
934 903 846
400 795
622 700 710
547 620
200 394
0
104
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
SAR in donor Number of reporting countries
Figure 46. Number of SAR in donors by reporting countries and year; 2011-2021 comparative data
The distribution of the 795 SAR in donors reported in 2021 for the three categories of tissues and cells
is presented in Figure 47.
Replacement Tissues & Cells (1)
0%
Haematopoietic Stem Cells (79)
10%
Reproductive Tissues & Cells (715)
90%
Figure 47. SAR in donors per category of donated tissue or cells (units); data 2021
The number of SAR per category of tissues and cells for the 17 countries that reported SAR in donors
in 2021 is represented in Figure 48.
315
300
250
200
141
100 84
68
50 28 24
17 22 17 16
2 2 3 56 1 1
02
0
Reproductive Haematopoietic Stem Cell Replacement
Figure 48. Number of SAR per category of tissue and cells and per country; data 2021
40
SAR in donors are distributed among the three categories of tissues and cells as follows:
• one case reported by Italy was associated with the donation of replacement tissues or cells
(0% of all SAR in donors).
• 79 cases (10%) of SAR in donors associated with HSC were reported by ten countries (BE, FI,
FR, DE, EL, IT, NL, PT, ES and SE). Thrombotic / embolic reactions and Other account for 49%
of SAR in donors of HSC, followed by autoimmune disease (11%), mechanical damage (11%),
infections (10%) and acute systemic toxicity during mobilization or collection (10%). Refer
to Figure 49 for all categories of reactions.
Thrombotic / embolic (11) 11 2
Reactions other than those listed above (28) 13 3 3
Neurological disease (2) 2
Musculoskeletal / joint affection (1) 1
Mechanical damage (from apheresis or bone marrow collection) (9) 6 111
Infection (8) 1
Autoimmune disease (9)
Allergic reaction (3) 2 1
Acute systemic toxicity during mobilization or collection (8)
0 5 10 15 20 25
General HSC Autologous Allogenic related Allogenic unrelated
Figure 49. SAR in donors by type of haematopoietic stem cells and type of reaction; data 2021
Reaction types for the most frequent categories of reactions are presented in Table 13 below.
Reaction category Reaction type
Reactions other than those listed above Hypocalcaemia, anaemia, chest pain not of cardiac or pulmonary
aetiology
Vasovagal reaction with syncope; seminoma; chest pain; upper
abdominal pain, vomiting, increased liver enzymes
No mobilization
Lipothymic episode with loss of consciousness during mobilization
Procedure suspended and target not reached
Neoplasm, high haematocrit, product destroyed during transport,
donor not starting G-CSF as scheduled
STEMI following donation; patient with cardiovascular history
Positive test to COVID-19 in asymptomatic and immunized patient
Positive serology test for Hepatitis E in donor before apheresis
Acute systemic toxicity during Ventricular tachycardia during anaesthesia induction
mobilization or collection
Mechanical damage (from apheresis or Catheter site pain, haematoma
bone marrow collection) Spleen rupture
Inadequate collection
Tissue compromised due to improper bag sealing
41
Thrombotic / embolic Increase in myocardial necrosis enzymes, hypokinesia of the septal
and inferior apex and severe anterior descending artery stenosis
Deep vein thrombosis
Table 13. SAR in donors of haematopoietic stem cells; data 2021
715 cases of SAR in donors (90%) were related to the donation of reproductive tissues or cells, of which
712 occurred following donation of oocytes, as shown in Table 13. Fourteen countries (BE, BG, HR, CZ,
EE, FR, DE, IE, IT, NL, PT, SI, ES and SE) reported. Most of the SAR in oocyte donors were OHSS (394
cases) and surgical complications (186 cases); the remaining cases included infectious complications,
ovarian torsion and Other types of SAR, as shown in Table 14 and Figure 50. Surgical complications
varied in severity, spanning from bleeding following oocyte aspiration, bladder injury/perforation with
urinary retention, intestinal obstruction and pelvic haemorrhage or peritonitis, to life threatening
complications. The SAR reported as Other include abdominal pain of various degrees of severity,
bleeding, haemoperitoneum, allergy to medicines, tubal/ectopic/multiple pregnancy, OHSS post
embryo transfer, etc.
Number
Tissue category Reaction type SAR %
of SAR
Oocytes • OHSS 394 55
• Surgical complications 186 26
• Other reactions 55 8
• Infection 51 7
• Ovarian torsion 29 4
Sperm • Surgical complications 2 0
Other reproductive tissues • Male genital organ cellulitis 1 0-
Table 14. Type of SAR in donors per subcategory of reproductive tissues and cells; data 2021
Distribution of SAR in donors by type of reaction in oocytes
Ovarian torsion (29) 21 8
Infections (50) 42 17
Reactions other than above (55) 37 513
Surgical Complications (184) 153 26 5
OHSS (394) 352 13 29
0 50 100 150 200 250 300 350 400 450
Partner or autologous Non-partner General
Figure 50. Distribution of SAR in donors by type of reaction in oocytes; data 2021
42
5 CONCLUSIONS
EU member and non-member states continued to support this initiative in 2021. Overall, the number
of reporting countries remained the same, with exception that the UK only provided data for Northern
Ireland following its withdrawal from the EU.
In general, the number of SAR reported since the initiative was launched in 2010 has trended upwards,
thanks to the commitment of countries to the vigilance program. In terms of non-reproductive tissues,
most of the SAR (81%) were classified as Other SAR (similar to previous years) indicating a need for
more precise classification of types or SAR related to non-reproductive tissues and cells. The same is
true for HSC and reproductive tissues and cells, where many SAR were reported as Other SAR due to
the limited number of listed categories available, indicating a need to expand the list of types of SAR
for each specific category of tissues and cells. The pattern for reproductive cells remained unchanged
from previous years: transmission of genetic diseases was once again the most frequently reported
SAR affecting offspring. It should be noted that the likelihood of transmitting multifactorial genetic
diseases from donor to offspring is sometimes difficult to assess, and these data should be evaluated
with caution.
The SAE analysis revealed specific areas of concern for each of the three categories of tissues and cells.
The high percentage of Other SAE related to replacement tissues and cells indicates that a more
concerted effort is required to improve the classification of SAE, which, in turn, would translate into
more accurate determination of causes and corrective/preventive actions. Microbial contamination
was mostly associated with HSC, while human error and system failure SAE were most commonly
associated with MAR procedures.
Despite the significant improvement in data completeness and accuracy over previous years, there are
still many inconsistencies among reporting countries in terms of data completeness and
classification/interpretation that makes it difficult to conduct more comprehensive data analysis and
draw reliable conclusions about safety and quality risks (trends) of tissues and cells. This implies the
need for additional concerted efforts to strengthen national vigilance systems and encourage the
implementation of a harmonised reporting dataset at the European level to enable the identification
of trends and risks associated with tissue and cell treatments.
Any interpretation of the analysis and results provided in this report should take into account the
limitations of the reporting exercise, notably the completeness and quality of the data reported.
43
Annex 1: Examples of SAE and assigned specification for replacement, HSC and reproductive tissues and cells
Replacement tissues and cells
Activity SAE specification Number Examples
of SAE
Donor Human error - Incorrect decision or omission 1 Tissue rejected in time to avoid implantation of unsuitable product
selection following the correct procedure Retrieval of tissue from donor with exclusion criteria
(15 / 9%) Human error - Other 1 Positive blood culture in donor
System failure - Inadequate process, 3 Electronic form not requiring critical health information resulting on release of tissue from donor
procedure or documentation with malignancy
Late receipt by TE of information from foreign procurement facility concerning infection in donor
Tissue or cell defect 10 Positive post-mortem COVID-19 test results; tissues rejected (pre-mortem test result negative)
Cells not meeting specification deemed unsuitable
Retrospective contraindication
Malignant disease transmission in recipient from tissue donor
Contraindication for donation identified post-transplantation
Testing Equipment failure 1 Malfunctioning testing instrument, delaying release of tissues
(28 / 16%) System failure - Inadequate process, 1 Invalid test performed with loss of one tissue
procedure or documentation
Tissue or cell defect 2 Donor test positive result for sexually transmitted disease (STD) pathogen
Human error - Incorrect decision or 6 Failure to perform SARS COV-2 testing timely with loss of ocular tissue
omission following the correct procedure
Other 18 Bacterial and fungal contamination of pre-implant culture or transport medium of ocular tissue
(cornea, scleral ring)
Identification of gram-positive bacteria in exudate post-skeletal tissue (bone) implant
Processing Equipment failure 1 Malfunctioning of HVAC system in clean room designated for processing requiring cease of activity
(19 / 11%) Human error – Following the wrong 1 Processing of tissue not as per specification resulting in delay of treatment
procedure
Human error - Incorrect decision or 1 Packaging of tissue not as per specification
omission following the correct procedure
Human error - Other 1 Loss of tissue (fell on the ground)
Materials 1 Improper sealing of packaging impacting sterility of internal package
44
Replacement tissues and cells
Activity SAE specification Number Examples
of SAE
System failure - Inadequate process, 2 Secondary packaging omitted (multiple tissues affected)
procedure or documentation Contamination of tissue with gram-positive bacteria (multiple tissues affected)
System failure - Other failure of the quality 1 Mechanical impurities detected in tissues
management system
Tissue or cell defect 11 Bacterial contamination of tissue after aseptic processing
Loss of tissue during processing through rupture
Tissue not meeting the specification resulting in cancellation of transplant
Graft failure due to tissue not having the required characteristic
Bacterial contamination of tissue
Other Human error - Incorrect decision or omission 3 Loss of tissue (fell on the ground)
(62 / 36%) following the correct procedure Tissue culture not performed prior to transplantation
Tissue from donor with malignancy implanted
Human error - Other, or no information to 4 Tissue transplanted after expiry date
assign the above options Tissue splitting with risk of losing traceability
Missing tissue with loss of traceability
System failure - Inadequate process, 1 Contamination of tissue during manipulation in the operating theatre
procedure or documentation
System failure - Staffing, workload or skill- 1 Lack of communication resulting in operating theatre being unavailable for scheduled transplant;
mix transplant cancellation
Tissue or cell defect 50 Bacterial contamination of tissue
Malignant disease transmission in recipient from tissue donor (discovered months after transplant)
Post donation information about malignancy in donor
Positive microbiological test results (multiple tissues)
Other 3 Fungal contamination of tissue identified post-transplantation
Bacterial and fungal contamination of pre-implant culture
45
Haematopoietic stem cells
Activity SAE specification Number Examples
of SAE
Procurement Equipment failure 2 Out-of-specification test result
(106 / 37%) Malfunction of collection set
Human error - Incorrect decision or omission 2 Microbial contamination of HSC
following the correct procedure Non-conforming apheresis product
Materials 3 Difficulties during collection due to malfunctioning equipment
System failure - Inadequate process, 13 Inadequate assessment of patient’s peripheral veins prevented collection of autologous HSC
procedure or documentation Improper sampling for quality control resulting in an overestimate of cell amount
Incomplete information and documentation provided by international donor centre
Insufficient cell count
Positive test result for bacteria (8 SAE)
Non-conforming HSC distributed due to lack of procedure
System failure - Staffing, workload or skill- 1 Processing and procurement temporarily paused
mix
Tissue or cell defect 78 Non-conforming imported bone marrow; processing did not render it suitable for use
Bacterial contamination of HSC (57 SAE)
HSC not meeting the specification (low cell count, low cell viability after thawing)
HSC not meeting the specification (Low cell count and viability of collected cells)
Non-conforming HSC (presence of clots of unknown cause); alternate type of HSC administered
subsequently
Bacterial contamination of apheresis product requiring new apheresis procedure
Other 7 Bacterial contamination (6 SAE)
Contaminated HSC were released for distribution and were transplanted before test results were
available
Processing Equipment failure 8 Power outage (freezer impacted)
(100 / 34%) Plant utility system malfunction resulted in a significant increase in the cell therapy unit
temperature
Stem cell container deterioration ("bag rupture”) during thawing
Defective freezer bag resulting in loss of cells
Centrifuge malfunction
46
Haematopoietic stem cells
Activity SAE specification Number Examples
of SAE
Human error - Incorrect decision or omission 3 Incorrect operating parameters set-up resulting in low yield of cells
following the correct procedure Inadvertently leaving a pocket in freezer
“presence of gram germ in lymphoapheresis product infused to the patient” (ES) contaminated HSC
infused?
Human error – Other 1 Sterility of HSC potentially compromised due to container integrity issue; cells discarded with no
consequence
Materials 10 “product error in stem cells freezing bag”
Failure of process step with loss of autologous HSC “failure of red blood cell depletion before pre-
freezing”
Bacterial contamination of HSC
Circuit break or container (pocket) leak
Non-conforming product (low cell viability after thawing)
“CBU pocket freezing program error”
Other 5 HSC destroyed based on positive control of operator’s fingers
Contamination
False positive result of first quality control
Processing delayed due to late delivery of materials as a consequence of a strike in another country
System failure - Inadequate process, 10 “Anomaly during the identification process”
procedure or documentation Improper selection of container for cell collection
Use of expired critical chemical (DMSO)
“Concentration error of DLI graft delivered and prepared from cryopreserved HSC” FR
“Set error for dilutions of a mononuclear cell graft”
“Positive test for Cutibacterium acnes” DE
System failure - Other failure of the 1 Bacterial contamination of HSC
quality management system
System failure - Training or education 4 Inadvertent destruction of HSC by operator due to lack of knowledge
HSC destroyed based on positive control of operator’s fingers
DMSO omitted (cryopreservation)
47
Haematopoietic stem cells
Activity SAE specification Number Examples
of SAE
Tissue or cell defect 58 Bacterial contamination of HSC (multiple)
Exceptional release of autologous unit of HSC with bacterial contamination; no infection in recipient
Cell viability affected by a combination of factors, transport included
Non-conforming product (insufficient cell quantity; low cell viability after thawing – 35 SAE)
Non-conforming product following thawing (bone marrow aggregates)
Aggregates formation during cryopreservation
Clots and aggregated formed during deplasmation required manual filtration that ended on
significant loss of cells
Non-conforming product (insufficient cells collected)
Testing System failure - Inadequate process, 3 Omission to confirm virological testing
(19 / 7%) procedure or documentation
Tissue or cell defect 3 Positive test result (marker of transmissible infection present)
Other 13 Positive test results
48
Reproductive tissues and cells
Activity SAE specification Number Examples
of SAE
Processing Equipment failure 12 Loss of cells during transport from one TE to another
(93 / 40%) Incubator power outage; cells not impacted
Loss of oocytes
Sensor failure during cell freezing
Incubator incident (increase in O2 level; drop in temperature)
Incorrect distribution of gas in incubators
Cryotube deterioration; loss of cell sample
Power outage in microinjection microscope preventing assessment of cells
Human error - Incorrect decision or omission 14 Failure to perform task without complete loss of cycle for recipient
following the correct procedure Inadvertent destruction of cells due to incorrect entry made in the patient’s electronic file
Incorrect assumption about the status of cells and omission of banking of straws; cells loss
Identification error (label)
Partial processing of cells (some cells forgotten)
Failure to follow instructions (embryo not frozen; transfer of incorrect type of cell)
Degeneration of oocytes due to insufficient oil drops to cover the culture medium; patient cycle
affected
Human error – Other 21 Operator manipulation error resulting in loss of cells
Only embryo lost during processing (plate falling to the ground)
Mix-up of gametes with loss of traceability
Quarantined gametes used) no information on partner or donor oocyte)
Mix-up of sperm from two different donors; loss of gametes
Handling incidents (excluding falls)
Loss of traceability of two embryos
Embryo compromised irreversibly due to lack of oil
Human error - Following the wrong 5 Handling incidents (excluding falls)
procedure Non-compliance with prescription instructions (incorrect embryo transferred)
Inadvertent discarding of cell by placing it in the incorrect disc (only available oocyte)
Materials 5 Incorrect labelling of culture dishes ending up in loss of the cycle by multiple patients
Material fall
Handling incidents (excluding falls)
49
Reproductive tissues and cells
Activity SAE specification Number Examples
of SAE
Other 5 Only available embryo lost during thawing procedure (blastocyst remaining attached to the pipette)
Only available embryo lost during transfer (degraded blastocyst while trying to detach it from the
pipette)
Material fall
Culture contamination
Bacterial growth during incubation; bacteria from donor
System failure - Inadequate process, 14 Identification error (vial label)
procedure or documentation Not following prescription instruction (request for straw instead of donor insemination)
Identification error (culture dish label); mix-up of gametes
Non-compliance with prescription instruction; erroneous freezing of cells
Defects in the management of thawing planning
Transcription error on the transfer sheet
Handling incidents (excluding falls)
Non-compliance with prescription instructions (incorrect embryo transferred)
Inappropriate use of a product during vitrification
Accidentally discarded cells (oocytes)
Contamination of dish with cells of a different type
System failure - Other failure of the quality 13 Mix-up of cells identified (cells from two donors collected in the same tube) at receipt on tissue
management system bank; one patient was affected by the need to destroy cells intended for treatment
Misplacement of one patient’s cells (embryos) in an incubator container destined for another
patient; no new box possible for affected patient due to lack of balance medium
Inadvertently discarded cell (embryo) during transfer to new culture medium
Cells development impaired (mitotic arrest due to hyperosmotic medium; insufficient oil droplets
to cover culture medium)
Culture contamination
Storage tank overloaded; while retrieving a vial for thawing, vials with another patient’s material
fell
System failure - Training or education 1 Cells incubated in out of order equipment CO2 and O2 turned off); treatment cycle lost
System failure - Staffing, workload or skill- 2 Failed vitrification of embryo; omission following the correct procedure
mix
50
Reproductive tissues and cells
Activity SAE specification Number Examples
of SAE
Tissue or cell defect 1 Contamination of culture medium
Donor Human error - Incorrect decision or omission 1 Omission of partner testing prior to IUI procedure; no consequence; post treatment testing results
selection following the correct procedure were negative
( 30/ 13%)
System failure - Inadequate process, 2 Positive test result for STD pathogen on a single sample from a given donor; no positive test results
procedure or documentation on samples from other donations; all straws from current donation destroyed
Omission of biological tests prior to IUI
Tissue or cell defect 22 Offspring of oocyte donor with psychiatric syndrome
Unknown genetic factor (non-partner donation)
Donor not disclosing previous donations and being permanently blocked by another bank
Genetic mutation not initially detected during screening testing
Donor diagnosed later with a multifactorial or possibly hereditary condition
Unknown at the time of donation that the donor was a carrier of a genetic condition; donor blocked
afterwards
Donor with congenital retinal dystrophy; embryos lost
Donor of oocyte carrier of genetic mutation
Other 5 Donor found to have donated in another sperm bank
Positive Zika serology test after biopsy
51